There are numerous drug therapies such as AZT, corticosteroids, cancer chemotherapeutic agents and hypercholesterolemic drugs, which are known to give rise to potentially serious side effects. These effects can be disabling and may last for the duration of the causative drug treatment or even after the drug treatment is complete, affecting not only an individual's capacity to work but also perform the simple tasks involved in day to day life. One particular group of drugs for which side effects are well recognised is the statins which are commonly used to treat hypercholesterolemia, a major cause of cardiovascular disease.
Cardiovascular disease is a term that encompasses a broad range of diseases and syndromes relating to the impairment of function of the heart and its associated network of blood vessels within the body. In spite of decades of declining death rate in the developed world cardiovascular disease is still the single most common cause of death, accounting for about one third of all deaths in the United States in 1997. Cardiovascular disease has many causes and is characterised by complex interactions between the heart, blood vessels, peripheral organs and the tissues. Some types of cardiovascular disease such as coronary heart disease or stroke can occur acutely and without warning, often with severe consequences, including death. Medically these are managed with aggressive treatment (drugs and surgery) followed by chronic treatment to prevent recurrence. Other types of cardiovascular disease such as hypertension (high blood pressure) and hyperlipidemia (high cholesterol) progress slowly, often without overt symptoms, and must be managed by diet and long-term chronic drug therapy.
Although cholesterol is an essential component of a healthy functioning body, being required, amongst other things, for the formation of functional membranes, steroid hormones and bile acids, excessive levels, particularly when associated with low density lipoproteins (LDLs), constitute a health risk. It is well established that there is a cause and effect relationship between hypercholesterolemia (excessive blood cholesterol levels) and disease and mortality from coronary artery (heart) disease. Of the deaths resulting from cardiovascular disease, more than three quarters can be attributed to arteriosclerosis and more specifically to atherosclerosis and its complications.
Arteriosclerosis is a generalized disease of the arteries that develops in a symptom free manner over many years. The most common form of arteriosclerosis is atherosclerosis which often gives rise to coronary heart disease, stroke, kidney disease and peripheral vascular disease. Elevated blood cholesterol concentration is a major contributing factor in the development of atherosclerosis. In situations of excessive blood cholesterol levels, cholesterol is gradually deposited on the artery walls together with other fats, resulting in build up which disrupts the free flow of blood, with potentially severe results. To lower high cholesterol levels, patients are treated with a range of drugs, the most common class of which are the statins. The statins, examples of which include atorvastatin, simvastatin, pravastatin, lovastatin, cerivastatin, fluvastatin and crestor, are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase). By inhibiting HMGCoA reductase and thus inhibiting the conversion of HMGCoA to mevalonate the statins act to decrease cholesterol blood/tissue levels.
The statins have also recently been reported to have potential utility in the treatment of a wide range of conditions including, but not limited to, dementia (The Lancet, 2000: 356; 1627-1631), various cancers, eg. prostate, skin, lung colon, bladder, uterus and kidney (Arch. Intern. Med. 2000, 160: 2363-2368), immune disorders, blood clotting disorders, osteoporosis, autoimmune diseases and cell cycle abnormalities.
However, there are a number of potentially serious side effects associated with statin therapy, including rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain, abdominal cramping, sleep disorder, rhinitis, sinusitis, dizziness, myopathy and fatigue. Of the contraindications for this group of drugs, two of the most common are fatigue and/or muscle pain (often referred to as “myalgia”). In severe cases, these symptoms may lead to the undesirable cessation of the vital therapy. In rare cases, severe muscle wastage (rhabdomyolysis) has been reported. The risk of adverse side effects during treatment with the statins is increased with concurrent administration of certain other drugs, such as cyclosporin, fabric acid derivatives (eg. gemfibrozil), erthyromycin, niacin and antifungals. Similar symptoms to those experienced by patients undergoing statin therapy may also be experienced by patients undergoing therapy with other drugs, or may be experienced as a result of a disease state.
Thus, there exists a need for the treatment of muscle pain and fatigue generally and especially for treatment of side effects associated with certain drug therapies, particularly the side effects associated with statin therapy.
It has now been found that uridine, its biological precursors or derivatives or a salt, ester, tautomer or analogue thereof (“uridine related compounds”) can usefully be administered in treating muscle pain and fatigue and for treating adverse side effects associated with some drug therapies. Uridine related compounds can therefore provide a useful adjunctive therapy to certain drug therapies.